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Neurodegenerative disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis and frontotemporal lobar dementia impose a pressing burden in most developed countries. Parkinson’s disease (PD) is clinically characterized as motor dysfunction disorder resulting from selective loss of substantia nigras dopaminergic neurons in the midbrain region. PD pathogenesis is multifactorial involving redox imbalance, glia-mediated inflammation and aggregated proteins accumulations that collectively lead to neuronal cell loss. Although traditional treatments relieve symptoms in early PD condition but they do not reverse the damage of dopaminergic neurons. Therefore, the present work was designed to investigate the neuroprotective efficacy of a novel combination of pioglitazone (PPAR-γ agonist) and curcumin in LPS-induced sub-acute dopaminergic neurodegeneration in rat model. We tested the effect of the combinations of pioglitazone (18 mg/kg. bw once daily) and curcumin (100 mg/kg. bw), in comparison to each one alone for five consecutive days before intranigral injection with lipopolysaccharide (LPS; 10 μg/2μl sterile saline/injection) against LPS-mediated neurotoxicity. The experimental results indicated that pretreatment with combined curcumin and pioglitazone, rather than each one alone, have powerful and synergistic anti-inflammatory effects by inhibiting the production of the cytokines TNF-α, IL-1β and IL-6 and inflammation-associated enzymes COX-2, iNOS through inhibition of NF-κB activity. Furthermore, this combination improved the brain antioxidant capacity by markedly elevating reduced …